rs727504887

chr11-47342127-C-Achr11-47342127-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP5

The NM_000256.3(MYBPC3):c.1654G>T(p.Ala552Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A552T) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MYBPC3 NM_000256.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 7.53

Genes affected

MYBPC3 (HGNC:7551): (myosin binding protein C3) MYBPC3 encodes the cardiac isoform of myosin-binding protein C. Myosin-binding protein C is a myosin-associated protein found in the cross-bridge-bearing zone (C region) of A bands in striated muscle. MYBPC3 is expressed exclusively in heart muscle and is a key regulator of cardiac contraction. Mutations in this gene are a frequent cause of familial hypertrophic cardiomyopathy. [provided by RefSeq, May 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a domain Ig-like C2-type 4 (size 89) in uniprot entity MYPC3_HUMAN there are 43 pathogenic changes around while only 10 benign (81%) in NM_000256.3
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-47342127-C-A is Pathogenic according to our data. Variant chr11-47342127-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 179473.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYBPC3	NM_000256.3	c.1654G>T	p.Ala552Ser	missense_variant	18/35	ENST00000545968.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYBPC3	ENST00000545968.6	c.1654G>T	p.Ala552Ser	missense_variant	18/35	5	NM_000256.3	P4
MYBPC3	ENST00000399249.6	c.1654G>T	p.Ala552Ser	missense_variant	17/34	5		A2
MYBPC3	ENST00000544791.1	c.1654G>T	p.Ala552Ser	missense_variant, NMD_transcript_variant	18/27	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 01, 2011	This variant is denoted Ala552Ser (aka A552S) at the protein level and c.1654 G>T at the cDNA level. The Ala552Ser variant in the MYBPC3 gene has not been reported as a disease-causing mutation, nor is it a known benign polymorphism to our knowledge. Ala552Ser results in a non-conservative amino acid substitution of a non-polar, hydrophobic Alanine residue with a polar Serine residue at a position that is conserved across species throughout evolution. In silico analysis predicts that Ala552Ser is possibly damaging to the structure/function of the protein and disease causing. A mutation affecting a nearby residue (Met555Thr) has been reported in association with HCM, further supporting the functional importance of this region of the protein. Furthermore, Ala552Ser was not detected in up to 600 alleles from control individuals of Caucasian and African American ancestry, indicating it is not a common benign variant in those populations. However, we cannot rule out that this change may be a benign variant. In summary, with the clinical and molecular information available at this time, we cannot definitively determine the clinical significance of the Ala552Ser variant, although evidence suggests it may be disease-causing. The variant is found in DCM panel(s). -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 04, 2019	The p.Ala552Ser variant in MYBPC3 has not been previously reported in individuals with cardiomyopathy and was absent from large population studies. Computational analyses (amino acid biochemical properties, conservation, AlignGVGD, PolyPhen2, and SIFT) suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. Additional information is needed to fully assess the clinical significance of this variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
CardioboostCm	Uncertain	0.12
BayesDel_addAF	Uncertain	0.024	T
BayesDel_noAF	Benign	-0.20
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.20	T;T;T
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	1.0	D;D;D
M_CAP	Uncertain	0.17	D
MetaRNN	Uncertain	0.73	D;D;D
MetaSVM	Benign	-0.57	T
MutationAssessor	Benign	0.94	L;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-1.5	N;.;N
REVEL	Benign	0.20
Sift	Benign	0.23	T;.;T
Sift4G	Uncertain	0.012	D;D;D
Vest4		0.75
MVP		0.90
MPC		0.79
ClinPred		0.90	D
GERP RS		5.7
Varity_R		0.25
gMVP		0.63

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs727504887; hg19: chr11-47363678;